Most protein or peptide drugs are short-lived and have often a short circulatory half-life in vivo. Considering that protein or peptide drugs are not absorbed orally, prolonged maintenance of therapeutically active drugs in the circulation is a desirable feature of obvious clinical importance.
An attractive strategy for improving clinical properties of protein or peptide drugs is a modification of the drugs with polymers e.g. polyalkylene-oxides (Roberts et al., Advan Drug Rev. 54, 459-476 (2002)) or polysaccharides like polysialic acid (Fernandes et al., Biochim Biophys Acta 1341, 26-34 (1997)), dextranes or hydroxyl alkyl starch. (All documents cited in the specification are incorporated by reference.)
The modification with poly(ethylene glycol) (PEG) has been known for a while. However, modification of proteins with PEG often leads to reduction of the activity of the protein.
Polysialic acid (PSA), also known as colominic acid (CA), is a natural occurring polysaccharide. It is a homopolymer of N-acetylneuraminic acid with α(2→8) ketosidic linkage and contains vicinal diol groups at its non-reducing end. PSA is negatively charged and is a natural constituent of the human body. It can easily be produced from bacteria in large quantities with pre-determined physical characteristics (U.S. Pat. No. 5,846,951). Being chemically and immunologically identical to polysialic acid in the human body, bacterial polysialic acid is non-immunogenic even when coupled to proteins. Unlike other polymers (e.g.; PEG), polysialic acid is biodegradable.
However, to date no therapeutic compound comprising a polypeptide conjugated to an acidic monosaccharide such as PSA is commercially available.
Short PSA polymeric chains with only 1-4 sialic acid units have also been synthesized (Kang et al., Chem. Commun., 227-228 (2000); Ress et al., Current Organic Synthesis 1, 31-46 (2004)).
Several hydrolysable or degradable linkers comprising PEG moieties have been suggested.
U.S. Pat. No. 6,515,100, describes PEG and related polymer derivatives, having weak, hydrolytically unstable linkages
U.S. Pat. No. 7,122,189 describes releasable PEG-linkers based on bis-N-2-hydroxyethyl glycine groups (bicine).
WO 04/089280 and WO 06/138572 describe hydrolysable fluorene-based PEG constructs.
After conjugation of these linkers to protein drugs, the protein-polymer conjugate can be regarded as a prodrug and the activity of the protein can be released from the conjugate via a controlled release mechanism. Using this concept improved pharmacokinetic properties of the drug can be obtained (Zhao et al., Bioconjugate Chem. 17, 341-351 (2006)).